3-Secretase BACE1 generates the A[unreadable] peptide involved in Alzheimer's disease (AD). Inhibition of BACE1 for towering A[unreadable] in Alzheimer's disease should be efficacious, however memory and emotional deficits in BACE1 knockout mice suggest that BACE1 inhibition may have side-effects. BACE1 levels are increased in Alzheimer's disease, suggesting that BACE1 elevation may play a role in Alzheimer's disease. We have shown that acute energy inhibition elevates BACE1 and in brains of Tg2576 mice, and our results indicate that chronic energy inhibition increases amyloid in Tg2576. We also observe elevated BACE1 around plaques in Alzheimer's disease, Tg2576, and in our new rapid amyloid model, 5XFAD mice. BACE1 elevation is not the result of increased BACE1 mRNA levels, suggesting a post- transcriptional mechanism. Two important questions arise: 1) Is BACE1 elevation involved in AD progression? 2) What is the molecular mechanism of BACE1 elevation? We will address these questions using a combination of molecular, cellular, and genetic analyses of human Alzheimer's disease, mouse Alzheimer's disease, and cell cultures. First, we will determine the molecular profile of BACE1 elevation in Alzheimer's disease. AD mice will then serve as in vivo models of BACE1 elevation, and cell cultures will be used to dissect molecular mechanism. We will then return to human Alzheimer's disease to verify the mechanism and use AD mice as experimental systems to interfere with the mechanism, block BACE1 elevation, and ameliorate amyloid pathology and memory deficits. Our overall hypothesis is that chronic cellular stress during AD results in sustained low-level increases of BACE1 and A[unreadable] that drive AD pathogenesis. AIM1: Determine the molecular profile of BACE1-positive plaques, and examine their relation to amyloid and to clinical AD and level of cognitive function assessed proximate to death. Aim2: Determine the molecular and cellular characteristics of the BACE1 elevation with age in APR transgenic mice and compare to human Alzheimer's disease. AIM3: Determine the molecular mechanism and pathway of the BACE1 elevation in vitro. Aim4: Validate the BACE1-elevating molecular pathway in Alzheimer's disease and APR transgenic brain and determine whether inhibition of the pathway in APR transgenic mice will slow progression of amyloid pathology. Alzheimer's disease is the leading cause of dementia in the elderly and there is no cure. The incidence of Alzheimer's disease will increase due to the aging population, indicating an impending AD epidemic. Inhibition of BACE1 elevation should reduce A[unreadable] without directly blocking BACE1 and thus may be efficacious without side-effects for Alzheimer's disease.